This invention relates to a series of phenylalanine derivatives, to compositions containing them, to processes for their preparation, and to their use in medicine.
Over the last few years it has become increasingly clear that the physical interaction of inflammatory leukocytes with each other and other cells of the body plays an important role in regulating immune and inflammatory responses [Springer, T A. Nature, 346, 425, (1990); Springer, T. A. Cell 76, 301, (1994)]. Many of these interactions are mediated by specific cell surface molecules collectively referred to as cell adhesion molecules.
The adhesion molecules have been sub-divided into different groups on the basis of their structure. One family of adhesion molecules which is believed to play a particularly important role in regulating immune and inflammatory responses is the integrin family. This family of cell surface glycoproteins has a typical non-covalently linked heterodimer structure. At least 14 different integrin alpha chains and 8 different integrin beta chains have been identified [Sonnenberg, A. Current Topics in Microbiology and Immunology, 184, 7, (1993)]. The members of the family are typically named according to their heterodimer composition although trivial nomenclature is widespread in this field. Thus the integrin termed xcex14xcex21 consists of the integrin alpha 4 chain associated with the integrin beta 1 chain, but is also widely referred to as Very Late Antigen 4 or VLA4. Not all of the potential pairings of integrin alpha and beta chains have yet been observed in nature and the integrin family has been subdivided into a number of subgroups based on the pairings that have been recognised [Sonnenberg, A. ibid].
The importance of cell adhesion molecules in human leukocyte function has been further highlighted by a genetic deficiency disease called Leukocyte Adhesion Deficiency (LAD) in which one of the families of leukocyte integrins is not expressed [Marlin, S. D. et al J. Exp. Med. 164, 855 (1986)]. Patients with this disease have a reduced ability to recruit leukocytes to inflammatory sites and suffer recurrent infections which in extreme cases may be fatal.
The potential to modify adhesion molecule function in such a way as to beneficially modulate immune and inflammatory responses has been extensively investigated in animal models using specific monoclonal antibodies that block various functions of these molecules [e.g. Issekutz, T. B. J. Immunol. 3394, (1992); Li, Z. et al Am. J. Physiol. 263, L723, (1992); Binns, R. M. et al J. Immunol. 157, 4094, (1996)]. A number of monoclonal antibodies which block adhesion molecule function are currently being investigated for their therapeutic potential in human disease.
One particular integrin subgroup of interest involves the xcex14 chain which can pair with two different beta chains xcex21 and xcex27 [Sonnenberg, A. ibid]. The xcex14xcex21 pairing occurs on many circulating leukocytes (for example lymphocytes, monocytes and eosinophils) although it is absent or only present at low levels on circulating neutrophils. xcex14xcex21 binds to an adhesion molecule (Vascular Cell Adhesion Molecule-1 also known as VCAM-1) frequently up-regulated on endothelial cells at sites of inflammation [Osborne, L. Cell, 62, 3, (1990)]. The molecule has also been shown to bind to at least three sites in the matrix molecule fibronectin [Humphries, M. J. et al. Ciba Foundation Symposium, 189, 177, (1995)]. Based on data obtained with monoclonal antibodies in animal models it is believed that the interaction between xcex14xcex21 and ligands on other cells and the extracellular matrix plays an important role in leukocyte migration and activation [Yednock, T. A. et al, Nature, 356, 63, (1992); Podolsky, D. K. et al. J. Clin. Invest. 92, 373, (1993); Abraham, W. M. et al. J. Clin. Invest. 93, 776, (1994)].
The integrin generated by the pairing of xcex14 and xcex27 has been termed LPAM-1 [Holzmann, B and Weissman, I. EMBO J. 8, 1735, (1989)] and like xcex14xcex21, binds to VCAM-1 and fibronectin. In addition, xcex14xcex27 binds to an adhesion molecule believed to be involved in the homing of leukocytes to mucosal tissue termed MAdCAM-1 [Berlin, C. et al, Cell: 74, 185, (1993)]. The interaction between xcex14xcex27 and MAdCAM-1 may also be important at sites of inflammation outside of mucosal tissue [Yang, X-D. et al, PNAS, 91, 12604 (1994)].
Regions of the peptide sequence recognised by xcex14xcex21 and xcex14xcex27 when they bind to their ligands have been identified. xcex14xcex21 seems to recognise LDV, IDA or REDV peptide sequences in fibronectin and a QIDSP sequence in VCAM-1 [Humphries, M. J. et al, ibid] whilst xcex14xcex27 recognises a LDT sequence in MAdCAM-1 [Briskin, M. J. et al, J. Immunol. 156, 719, (1996)]. There have been several reports of inhibitors of these interactions being designed from modifications of these short peptide sequences [Cardarelli, P. M. et al J. Biol. Chem. 269, 18668, (1994); Shroff, H. N. Bioorganic. Med. Chem. Lett. 6, 2495, (1996); Vanderslice, P. J. Immunol. 158, 1710, (1997)]. It has also been reported that a short peptide sequence derived from the xcex14xcex21 binding site in fibronectin can inhibit a contact hypersensitivity reaction in a trinitrochlorobenzene sensitised mouse [Ferguson, T. A. et al, PNAS 88, 8072, (1991)].
Since the alpha 4 subgroup of integrins are predominantly expressed on leukocytes their inhibition can be expected to be beneficial in a number of immune or inflammatory disease states. However, because of the ubiquitous distribution and wide range of functions performed by other members of the integrin family it is very important to be able to identify selective inhibitors of the alpha 4 subgroup.
We have now found a group of compounds which are potent and selective inhibitors of xcex14 integrins. Members of the group are able to inhibit xcex14 integrins such as xcex14xcex21 and/or xcex14xcex27 at concentrations at which they generally have no or minimal inhibitory action on a integrins of other subgroups. The compounds are thus of use in medicine, for example in the prophylaxis and treatment of immune or inflammatory disorders as described hereinafter.
Thus according to one aspect of the invention we provide a compound of formula (1) 
wherein
R is a carboxylic acid or a derivative thereof;
R1 is a hydrogen atom or a hydroxyl, straight or branched alkoxy or optionally substituted cycloaliphatic, polycycloaliphatic, hetero-cycloaliphatic, polyheterocycloaliphatic, aromatic or heteroaromatic group;
Alk1 is an optionally substituted aliphatic or heteroaliphatic chain;
L1 is a linker atom or group;
r and s, which may be the same or different, is each zero or an integer 1 provided that when r is zero R1 is an optionally substituted cycloaliphatic, polycycloaliphatic, polyheterocycloaliphatic, aromatic or heteroaromatic group;
Ra and Rb, which may be the same or different is each an atom or group xe2x80x94L2(CH2)pL3(Rc)q in which L2 and L3 is each a covalent bond or a linker atom or group, p is zero or the integer 1, q is an integer 1, 2 or 3 and Rc is a hydrogen or halogen atom or a group selected from straight or branched alkyl, xe2x80x94ORd [where Rd is a hydrogen atom or an optionally substituted straight or branched alkyl group], xe2x80x94SRd, xe2x80x94NRdRe, [where Re is as just defined for Rd and may be the same or different], xe2x80x94NO2,xe2x80x94CN, xe2x80x94CO2Rd, xe2x80x94SO3H, xe2x80x94SO2Rd, xe2x80x94OCO2Rd, xe2x80x94CONRdRe, xe2x80x94OCONRdRe, xe2x80x94CSNRdRe, xe2x80x94CORd, xe2x80x94N(Rd)CORe, N(Rd)CSRe, xe2x80x94SO2N(Rd)(Re), xe2x80x94N(Rd)SO2Re, xe2x80x94N(Rd)CONReRf [where Rf is a hydrogen atom or an optionally substituted straight or branched alkyl group], xe2x80x94N(Rd)CSNReRf or xe2x80x94N(Rd)SO2NReRf;
Alk2 is a straight or branched alkylene chain;
m is zero or an integer 1;
R2 is a hydrogen atom or a methyl group;
R3 is a hydrogen atom or a straight or branched alkyl group;
Ar is an optionally substituted aromatic group;
and the salts, solvates, hydrates and N-oxides thereof, for use in modulating cell adhesion.
The compounds of formula (1) are potent and selective inhibitors of xcex14 integrins. The ability of the compounds to act in this way may be simply determined by employing tests such as those described in the Examples hereinafter. In particular compounds of the invention are advantageously selective xcex14xcex21 inhibitors
The compounds of formula (1) are thus of use in modulating cell adhesion and in particular are of use in the prophylaxis and treatment of diseases or disorders involving inflammation in which the extravasation of leukocytes plays a role. The invention extends to such a use and to the use of compounds of formula (1) for the manufacture of a medicament for treating such diseases or disorders. Diseases or disorders of this type include inflammatory arthritis such as rheumatoid arthritis vasculitis or polydermatomyositis, multiple sclerosis, allograft rejection, diabetes, inflammatory dermatoses such as psoriasis or dermatitis, asthma and inflammatory bowel disease.
For the prophylaxis or treatment of disease the compounds of formula (1) may be administered as pharmaceutical compositions, and according to a further aspect of the invention we provide a pharmaceutical composition which comprises a compound of formula (1) together with one or more pharmaceutically acceptable carriers, excipients or diluents, for use in modulating cell adhesion, particularly in the prophylaxis and treatment of diseases or disorders involving inflammation as just described.
Pharmaceutical compositions for use according to the invention may take a form suitable for oral, buccal, parenteral, nasal, topical or rectal administration, or a form suitable for administration by inhalation or insufflation and the invention extends to the use of a compound of formula (1) in the manufacture of such formulations.
For oral administration, the pharmaceutical compositions may take the form of, for example, tablets, lozenges or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (e.g. pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers (e.g. lactose, microcrystalline cellulose or calcium hydrogen phosphate); lubricants (e.g. magnesium stearate, talc or silica); disintegrants (e.g. potato starch or sodium glycollate); or wetting agents (e.g. sodium lauryl sulphate). The tablets may be coated by methods well known in the art. Liquid preparations for oral administration may take the form of, for example, solutions, syrups or suspensions, or they may be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents, emulsifying agents, non-aqueous vehicles and preservatives. The preparations may also contain buffer salts, flavouring, colouring and sweetening agents as appropriate.
Preparations for oral administration may be suitably formulated to give controlled release of the active compound.
For buccal administration the compositions may take the form of tablets or lozenges formulated in conventional manner.
The compounds for formula (1) may be formulated for parenteral administration by injection e.g. by bolus injection or infusion. Formulations for injection may be presented in unit dosage form, e.g. in glass ampoule or multi dose containers, e.g. glass vials. The compositions for injection may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilising, preserving and/or dispersing agents. Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, e.g. sterile pyrogen-free water, before use.
In addition to the formulations described above, the compounds of formula (1) may also be formulated as a depot preparation. Such long acting formulations may be administered by implantation or by intramuscular injection.
For nasal administration or administration by inhalation, the compounds for use according to the present invention are conveniently delivered in the form of an aerosol spray presentation for pressurised packs or a nebuliser, with the use of suitable propellant, e.g. dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas or mixture of gases.
The compositions may, if desired, be presented in a pack or dispenser device which may contain one or more unit dosage forms containing the active ingredient. The pack or dispensing device may be accompanied by instructions for administration.
The quantity of a compound of formula (1) required for the prophylaxis or treatment of a particular condition will vary depending on the compound chosen, and the condition of the patient to be treated. In general, however, effective daily dosages may range from around 100 ng/kg to 100 mg/kg e.g. around 0.01 mg/kg to 40 mg/kg body weight for oral or buccal administration, from around 10 ng/kg to 50 mg/kg body weight for parenteral administration and around 0.05 mg to around 1000 mg e.g. around 0.5 mg to around 1000 mg for nasal administration or administration by inhalation or insufflation.
Particular compounds of formula (1) form a further feature of the invention and in a further aspect we therefore provide a compound of formula (1a): 
wherein
R is a carboxylic acid or a derivative thereof;
R1 is an optionally substituted cycloaliphatic, polycycloaliphatic, heterocycloaliphatic. polyheterocyclialiphatic, aromatic or heteroaromatic group;
Alk1 is an optionally substituted aliphatic or heteroaliphatic chain;
L1 is a linker atom or group;
r and s, which may be the same or different, is each zero or an integer 1; Ra and Rb, which may be the same or different is each an atom or group xe2x80x94L2(CH2)pL3(Rc)q in which L2 and L3 is each a covalent bond or a linker atom or group, p is zero or the integer 1, q is an integer 1, 2 or 3 and Rc is a hydrogen or halogen atom or a group selected from straight or branched alkyl, ORd [where Rd is a hydrogen atom or an optionally substituted straight or branched alkyl group], xe2x80x94SRd, xe2x80x94NRdRe, [where Reis as just defined for Rd and may be the same or different], xe2x80x94NO2,xe2x80x94CN, xe2x80x94CO2Rd, xe2x80x94SO3H, xe2x80x94SO2Rd, xe2x80x94OCO2Rd, xe2x80x94CONRdRe, xe2x80x94OCONRdRe, xe2x80x94CSNRdRe, xe2x80x94CORd, xe2x80x94N(Rd)CORe, N(Rd)CSRe, xe2x80x94SO2N(Rd)(Re), xe2x80x94N(Rd)SO2Re, xe2x80x94N(Rd)CONReRf [where Rf is a hydrogen atom or an optionally substituted straight or branched alkyl group], xe2x80x94N(Rd)CSNReRf or xe2x80x94N(Rd)SO2NReRf;
Alk2 is a straight or branched alkylene chain;
m is zero or an integer 1;
R2 is a hydrogen atom or a methyl group;
R3 is a hydrogen atom or a straight or branched alkyl group;
Ar is an optionally substituted aromatic group;
and the salts, solvates, hydrates and N-oxides thereof.
It will be appreciated that compounds of formulae (1) and (1a) may have one or more chiral centres. Where one or more chiral centres is present, enantiomers or diastereomers may exist, and the invention is to be understood to extend to all such enantiomers, diasteromers and mixtures thereof, including racemates. Formulae (1) and (1a) and the formulae hereinafter are intended to represent all individual isomers and mixtures thereof, unless stated or shown otherwise.
In the compounds of formulae (1) and (1a), derivatives of the carboxylic acid group R include carboxylic acid esters and amides. Particular esters and amides include xe2x80x94CO2Alk4 and xe2x80x94CON(R4)2 groups as described herein.
When in the compounds of formulae (1) and (1a) L1 is present as a linker atom or group it may be any divalent linking atom or group. Particular examples include xe2x80x94Oxe2x80x94 or xe2x80x94Sxe2x80x94 atoms or xe2x80x94C(O)xe2x80x94, xe2x80x94C(O)Oxe2x80x94, xe2x80x94C(S)xe2x80x94, xe2x80x94S(O)xe2x80x94, xe2x80x94S(O)2xe2x80x94, xe2x80x94N(R4)xe2x80x94 [where R4 is a hydrogen atom or a straight or branched alkyl group], xe2x80x94CON(R4)xe2x80x94, xe2x80x94OC(O)N(R4)xe2x80x94, xe2x80x94CSN(R4)xe2x80x94, xe2x80x94N(R4)COxe2x80x94, xe2x80x94N(R4)C(O)Oxe2x80x94, xe2x80x94N(R4)CSxe2x80x94, xe2x80x94S(O)N(R4)xe2x80x94, xe2x80x94S(O)2N(R4)xe2x80x94, xe2x80x94N(R4)S(O)xe2x80x94, xe2x80x94N(R4)S(O)2xe2x80x94, xe2x80x94N(R4)CON(R4)xe2x80x94, xe2x80x94N(R4)CSN(R4)xe2x80x94, xe2x80x94N(R4)SON(R4)xe2x80x94 or xe2x80x94N(R4)SO2N(R4)xe2x80x94 groups. Where the linker group contains two R4 substituents, these may be the same or different.
Alk2 in the compounds of formulae (1) and (1a) may be for example a straight or branched C1-3alkylene chain. Particular examples include xe2x80x94CH2xe2x80x94, xe2x80x94CH(CH3)xe2x80x94, xe2x80x94C(CH3)2xe2x80x94 and xe2x80x94(CH2)2xe2x80x94.
When R3 and/or R4 in the compounds of formula (1) is a straight or branched alkyl group it may be a straight or branched C1-6 alkyl group, e.g. a C1-3 alkyl group such as a methyl or ethyl group.
When Alk1 in compounds of formula (1) is an optionally substituted aliphatic chain it may be an optionally substituted C1-10 aliphatic chain. Particular examples include optionally substituted straight or branched C1-6 alkylene, C2-6 alkenylene, or C2-6 alkynylene chains.
Heteroaliphatic chains represented by Alk1 include the aliphatic chains just described but with each chain additionally containing one, two, three or four heteroatoms or heteroatom-containing groups. Particular heteroatoms or groups include atoms or groups L4 where L4 is as defined above for L1 when L1 is a linker atom or group. Each L4 atom or group may interrupt the aliphatic chain, or may be positioned at its terminal carbon atom to connect the chain to the atom or group R1.
Particular examples of aliphatic chains represented by Alk1 include optionally substituted xe2x80x94CH2xe2x80x94, xe2x80x94CH2CH2xe2x80x94, xe2x80x94CH(CH3)xe2x80x94, xe2x80x94C(CH3)2xe2x80x94, xe2x80x94(CH2)2CH2xe2x80x94, xe2x80x94CH(CH3 )CH2xe2x80x94, xe2x80x94(CH2)3CH2xe2x80x94, xe2x80x94CH(CH3 )CH2CH2xe2x80x94, xe2x80x94CH2CH(CH3)CH2xe2x80x94, xe2x80x94C(CH3)2CH2xe2x80x94, xe2x80x94(CH2)4CH2xe2x80x94, xe2x80x94(CH2)5CH2xe2x80x94, xe2x80x94CHCHxe2x80x94, xe2x80x94CHCHCH2xe2x80x94, xe2x80x94CH2CHCHxe2x80x94, xe2x80x94CHCHCH2CH2xe2x80x94, xe2x80x94CH2CHCHCH2xe2x80x94, xe2x80x94(CH2)2CHCHxe2x80x94, xe2x80x94CCxe2x80x94, xe2x80x94CCCH2xe2x80x94, xe2x80x94CH2CCxe2x80x94, xe2x80x94CCCH2CH2xe2x80x94, xe2x80x94CH2CCCH2xe2x80x94, or xe2x80x94(CH2)2CCxe2x80x94 chains. Where appropriate each of said chains may be optionally interrupted by one or two atoms and/or groups L4 to form an optionally substituted heteroaliphatic chain. Particular examples include optionally substituted xe2x80x94L4CH2xe2x80x94, xe2x80x94CH2L4CH2xe2x80x94, xe2x80x94L4(CH2)2xe2x80x94, xe2x80x94CH2L4(CH2)2xe2x80x94, xe2x80x94(CH2)2L4CH2xe2x80x94, xe2x80x94L4(CH2)3xe2x80x94 and xe2x80x94(CH2)2L4(CH2)2xe2x80x94 chains.
The optional substituents which may be present on aliphatic or heteroaliphatic chains represented by Alk1 include one, two, three or more substituents selected from halogen atoms, e.g. fluorine, chlorine, bromine or iodine atoms, or hydroxyl, C1-6alkoxy, e.g. methoxy or ethoxy, thiol, C1-6alkylthio e.g. methylthio or ethylthio, amino or substituted amino groups. Substituted amino groups include xe2x80x94NHR4 and xe2x80x94N(R4)2 groups where R4 is a straight or branched alkyl group as defined above. Where two R4 groups are present these may be the same or different. Particular examples of substituted chains represented by Alk1 include those specific chains just described substituted by one, two, or three halogen atoms such as fluorine atoms, for example chains of the type xe2x80x94CH(CF3)xe2x80x94, xe2x80x94C(CF3)2xe2x80x94CH2CH(CF3)xe2x80x94, xe2x80x94CH2C(CF3)2xe2x80x94, xe2x80x94CH(CF3)xe2x80x94 and xe2x80x94C(CF3)2CH2.
Alkoxy groups represented by R1 in compounds of formula (1) include straight of branched C1-6alkoxy groups such as methoxy and ethoxy groups.
When R1 is present in compounds of formulae (1) and (1a) as an optionally substituted cycloaliphatic group it may be an optionally substituted C3-10 cycloaliphatic group. Particular examples include optionally substituted C3-10 cycloalkyl, e.g. C3-7cycloalkyl, C3-10 cycloalkenyl e.g. C3-7cycloalkenyl or C3-10cycloalkynyl e.g. C3-7cycloalkynyl groups.
Optionally substituted heterocycloaliphatic groups represented by R1 include the optionally substituted cycloaliphatic groups just described for R1 but with each group additionally containing one, two, three or four heteroatoms or heteroatom-containing groups L2 as just defined.
Optionally substituted polycycloaliphatic groups represented by R1 include optionally substitued C7-10 bi- or tricycloalkyl or C7-10bi- or tricycloalkenyl groups. Optionally substituted polyheterocycloaliphatic groups represented by R1 include the optionally substituted polycycloalkyl groups just described, but with each group additionally containing one, two, three or four L2 atoms or groups.
Particular examples of R1 cycloaliphatic, polycycloaliphatic, heterocyclo-aliphatic and polyheterocycloaliphatic groups include optionally substituted cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, 2-cyclobuten-1-yl, 2-cyclopenten-1-yl, 3-cyclopenten-1-yl, adamantyl, norbornyl, norbornenyl, pyrroline, e.g. 2- or 3-pyrrolinyl, pyrrolidinyl, pyrrolidinone, oxazolidinyl, oxazolidinone, dioxolanyl, e.g. 1,3-dioxolanyl, imidazolinyl, e.g. 2-imidazolinyl, imidazolidinyl, pyrazolinyl, e.g. 2-pyrazolinyl, pyrazolidinyl, thiazolinyl, thiazolidinyl, pyranyl, e.g. 2- or 4-pyranyl, piperidinyl, piperidinone, 1,4-dioxanyl, morpholinyl, morpholinone, 1,4-dithianyl, thiomorpholinyl, piperazinyl, 1,3,5-trithianyl, oxazinyl, e.g. 2H-1,3-, 6H-1,3-, 6H-1,2-, 2H-1,2- or 4H-1,4- oxazinyl, 1,2,5-oxathiazinyl, isoxazinyl, e.g. o- or p-isoxazinyl, oxathiazinyl, e.g. 1,2,5 or 1,2,6-oxathiazinyl, or oxadiazinyl e.g. 1,3,5-oxodiazinyl groups.
The optional substituents which may be present on the R1 cycloaliphatic, polycycloaliphatic, heterocycloaliphatic or polyheterocycloaliphatic groups include one, two, three or more substituents represented by R5 in which R5 is selected from halogen atoms, e.g. fluorine, chlorine, bromine or iodine atoms, or C1-6alkyl, e.g. methyl or ethyl, haloC1-6alkyl, e.g. halomethyl or haloethyl such as difluoromethyl or trifluoromethyl, hydroxyl, C1-6alkoxy, e.g. methoxy or ethoxy, haloC1-6alkoxy, e.g. halomethoxy or haloethoxy such as difluoromethoxy or trifluoromethoxy, thiol, C1-6alkylthio e.g. methylthio or ethylthio, xe2x80x94N(R4)2, xe2x80x94CN, xe2x80x94CO2R4, xe2x80x94NO2, xe2x80x94CON(R4)2, xe2x80x94CSN(R4)2, xe2x80x94COR4, xe2x80x94CSN(R4)2, xe2x80x94N(R4)COR4, xe2x80x94N(R4)CSR4, xe2x80x94SO2N(R4)2, xe2x80x94N(R4)SO2R4, xe2x80x94N(R4)CON(R4)2, xe2x80x94N(R4)CSN(R4) and xe2x80x94N(R4)SO2N(R4)2, groups. In these substituents the group R4 when present is a hydrogen atom or a straight or branched alkyl group as defined above. Where more than one R4 group is present in a substituent each group may be the same or different. The substituent may be present on any available carbon atom or where appropriate any nitrogen atom, in the R1 group.
In the compounds of formulae (1) and (1a), optionally substituted aromatic groups represented by the group R1 include for example monocyclic or bicyclic fused ring C6-12 aromatic groups, such as phenyl, 1- or 2- naphthyl, 1- or 2-tetrahydronaphthyl, indanyl or indenyl groups, optionally substituted by one, two, three or more L2(CH2)pL3(Rc)q atoms or groups, where L2, L3, p and q are as previously defined and Rc is as previously defined but is other than a hydrogen atom when L2 and L3 is each a covalent bond and p is zero.
Optionally substituted heteroaromatic groups, represented by the group R1 in compounds of formulae (1) and (1a) include for example optionally substituted C1-9 heteroaromatic groups containing for example one, two, three or four heteroatoms selected from oxygen, sulphur or nitrogen atoms. In general, the heteroaromatic groups may be for example monocyclic or bicyclic fused ring heteroaromatic groups. Monocyclic heteroaromatic groups include for example five- or six-membered heteroaromatic groups containing one, two, three or four heteroatoms selected from oxygen, sulphur or nitrogen atoms. Bicyclic heteroaromatic groups include for example nine- to thirteen-membered fused-ring heteroaromatic groups containing one, two or more heteroatoms selected from oxygen, sulphur or nitrogen atoms.
Particular examples of heteroaromatic groups of these types include optionally substituted pyrrolyl, furyl, thienyl, imidazolyl, N-C1-6aimidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,3,4-thiadiazole, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, 1,3,5-triazinyl, 1,2,4-triazinyl, 1,2,3-triazinyl, benzofuryl, (2,3-dihydro]-benzofuryl, benzothienyl, benzotriazolyl, indolyl, isoindolyl, benzimidazolyl, imidazo[1,2-alpyridyl, benzothiazolyl, benzoxazolyl, benzopyranyl, [3,4-dihydro]benzopyranyl, quinazolinyl, naphthyridinyl, pyrido[3,4-b]pyridyl, pyrido[3,2-b]pyridyl, pyrido[4,3-b]pyridyl, quinolinyl, isoquinolinyl, tetrazolyl, 5,6,7,8-tetrahydroquinolinyl, 5,6,7,8-tetrahydroisoquinolinyl, and imidyl, e.g. succinimidyl, phthalimidyl, or naphthalimidyl such as 1,8-naphthalimidyl.
Optional substituents which may be present on R1 heteroaromatic groups include one, two, three or more xe2x80x94L2(CH2)pL3(Rc)q atoms or groups as just defined.
Examples of the substituents represented by Ra and Rb in compounds of formula (1) and which may be present on aromatic or heteroaromatic groups represented by R1 include atoms or groups xe2x80x94L2(CH2)pLRc, xe2x80x94L2(CH2)pRc, xe2x80x94L2Rc, xe2x80x94(CH2)pRc and Rc wherein L2, (CH2)p, L and Rc are as defined above. Particular examples of such substituents include xe2x80x94L2CH2L2Rc, xe2x80x94L2CH(CH3)L3Rc, xe2x80x94L2(CH2)2L3Rc, xe2x80x94L2CH2Rc, xe2x80x94L2xe2x80x94L2(CH2)2Rc, xe2x80x94CH2Rc, xe2x80x94CH(CH3)Rc and xe2x80x94(CH2)2Rc groups.
Thus each of Ra and Rb and, where present, substituents on R1 and aromatic or heteroaromatic groups in compounds of the invention may be for example selected from a hydrogen atom, a halogen atom, e.g. a fluorine, chlorine, bromine or iodine atom, or a C1-6alkyl, e.g. methyl, ethyl, n-propyl, i- propyl, n-butyl or t-butyl, C1-6alkylamino, e.g. methylamino or ethylamino, C1-6hydroxyalkyl, e.g. hydroxymethyl, hydroxyethyl or xe2x80x94C(OH)(CF3)2, carboxyC1-6alkyl, e.g. carboxyethyl, C1-6alkylthio e.g. methylthio or ethylthio, carboxyC1-6alkylthio, e.g. carboxymethylthio, 2-carboxyethylthio or 3-carboxypropylthio, C1-6alkoxy, e.g. methoxy or ethoxy, hydroxyC1-6alkoxy, e.g. 2-hydroxyethoxy, haloC1-6alkyl, e.g. xe2x80x94CF3, xe2x80x94CHF2, CH2F, haloC1-6alkoxy, e.g. xe2x80x94OCF3,xe2x80x94OCHF2,xe2x80x94OCH2F, C1-6alkylamino, e.g. methylamino or ethylamino, amino (xe2x80x94NH2), aminoC1-6alkyl, e.g. aminomethyl or aminoethyl, C1-6dialkylamino, e.g. dimethylamino or diethylamino, C1-6alkylaminoC1-6alkyl, e.g. ethylaminoethyl, C1-6dialkylaminoC1-6alkyl, e.g. diethylaminoethyl, aminoC1-6alkoxy, e.g. aminoethoxy, C1-6alkylaminoC1-6alkoxy, e.g. methylaminoethoxy, C1-6dialkylaminoC1-6alkoxy, e.g. dimethylaminoethoxy, diethylaminoethoxy, isopropylaminoethoxy, or dimethylaminopropoxy, nitro, cyano, amidino, hydroxyl (xe2x80x94OH), formyl (HC(O)xe2x80x94], carboxyl (xe2x80x94CO2H), xe2x80x94CO2R12, C1-6alkanoyl e.g. acetyl, thiol (xe2x80x94SH), thioC1-6alkyl, e.g. thiomethyl or thioethyl, sulphonyl (xe2x80x94SO3H), C1-6alkylsulphonyl, e.g. methylsulphonyl, aminosulphonyl (xe2x80x94SO2NH2), C1-6alkylaminosulphonyl, e.g. methylaminosulphonyl or ethylaminosulphonyl, C1-6dialkylaminosulphonyl, e.g. dimethylaminosulphonyl or diethylaminosulphonyl, phenylaminosulphonyl, carboxamido (xe2x80x94CONH2), C1-6alkylaminocarbonyl, e.g. methylaminocarbonyl or ethylaminocarbonyl, C1-6dialkylaminocarbonyl, e.g. dimethylaminocarbonyl or diethylaminocarbonyl, aminoC1-6alkylaminocarbonyl, e.g. aminoethylaminocarbonyl, C1-6dialkylaminoC1-6alkylaminocarbonyl, e.g. diethylaminoethylaminocarbonyl, aminocarbonylamino. C1-6alkylaminocarbonylamino, e.g. methylaminocarbonylamino or ethylaminocarbonylamino, C1-6dialkylaminocarbonylamino, e.g. dimethylamino-carbonylamino or diethylaminocarbonylamino, C1-6alkylaminocabonylC1-6alkylamino, e.g. methylaminocarbonylmethylamino, aminothiocarbonyl-amino, C1-6alkylaminothiocarbonylamino, e.g. methylaminothiocarbonylamino or ethylaminothiocarbonylamino, C1-6dialkylaminothiocarbonylamino, e.g. dimethylaminothiocarbonylamino or diethylaminothiocarbonylamino, C1-6alkylaminothiocarbonylC1-6alkylamino, e.g. ethylaminothiocarbonylmethylamino, C1-6alkylsulphonylamino, e.g. methylsulphonylamino or ethylsulphonylamino, C1-6dialkylsulphonylamino, e.g. dimethylsulphonyl-amino or diethylsulphonylamino, aminosulphonylamino (xe2x80x94NHSO2NH2), C1-6alkylaminosulphonylamino, e.g. methylaminosulphonylamino or ethylaminosulphonylamino, C1-6dialkylaminosulphonylamino, e.g. dimethylaminosulphonylamino or diethylaminosulphonylamino, C1-6alkanoylamino, e.g. acetylamino, aminoC1-6alkanoylamino e.g. aminoacetylamino, C1-6dialkylaminoC1-6alkanoylamino, e.g. dimethylaminoacetylamino, C1-6alkanoylaminoC1-6alkyl, e.g. acetylaminomethyl, C1-6alkanoylaminoC1-6alkylamino, e.g. acetamidoethylamino, C1-6alkoxycarbonylamino, e.g. methoxycarbonylamino, ethoxycarbonylamino or t-butoxycarbonylamino group.
Aromatic groups represented by the group Ar in compounds of formulae (1) and (1a) include optionally substituted monocyclic of bicyclic fused ring C1-6 aromatic groups. Particular examples include optionally substituted phenyl, 1- or 2-naphthyl, 1- or 2- tetrahydronaphthyl, indanyl or indenyl groups.
Optional substituents present on the aromatic groups represented by Ar include one, two, three or more substituents, each selected from an atom or group R6 in which R6 is xe2x80x94R6a or xe2x80x94Alk3(R6a)m, where R6a is a halogen atom, or an amino (xe2x80x94NH2), substituted amino, nitro, cyano, amidino, hydroxyl (xe2x80x94OH), substituted hydroxyl, formyl, carboxyl (xe2x80x94CO2H), esterified carboxyl, thiol (xe2x80x94SH), substituted thiol, xe2x80x94COR7 [where R7 is an xe2x80x94Alk3(R6a)m, aryl or heteroaryl group], xe2x80x94CSR7, xe2x80x94SO3H, xe2x80x94SO2R7 xe2x80x94SO2NH2, xe2x80x94SO2NHR7 SO2N(R7)2, xe2x80x94CONH2, xe2x80x94CSNH2, xe2x80x94CONHR7, xe2x80x94CSNHR7, xe2x80x94CON[R7]2, xe2x80x94CSN(R7)2, xe2x80x94N(R4)SO2R7, xe2x80x94N(SO2R7)2, xe2x80x94NH(R4)SO2NH2, xe2x80x94N(R4)SO2NHR7, xe2x80x94N(R4)SO2N(R7)2, xe2x80x94N(R4)COR7, xe2x80x94N(R4)CON(R7)2, xe2x80x94N(R4)CSN(R7)2, xe2x80x94N(R4)CSR7, xe2x80x94N(R4)C(O)OR7, xe2x80x94SO2NHet1 [where xe2x80x94NHet1 is an optionally substituted C5-7cyclicamino group optionally containing one or more other xe2x80x94Oxe2x80x94 or xe2x80x94Sxe2x80x94 atoms or xe2x80x94N(R4)xe2x80x94, xe2x80x94C(O)xe2x80x94 or xe2x80x94C(S)xe2x80x94 groups], xe2x80x94CONHet1, xe2x80x94CSNHet1, xe2x80x94N(R4)SO2NHet1, xe2x80x94N(R4)CONHet1, xe2x80x94N(R4)CSNHet1, xe2x80x94SO2N(R4)Het2 [where Het2 is an optionally substituted monocyclic C5-7carbocyclic group optionally containing one or more xe2x80x94Oxe2x80x94 or xe2x80x94Sxe2x80x94 atoms or xe2x80x94N(R4)xe2x80x94, xe2x80x94C(O)xe2x80x94 or xe2x80x94C(S)xe2x80x94 groups], xe2x80x94CON(R4)Het2, xe2x80x94CSN(R4)Het2, xe2x80x94N(R4)CON(R4)Het2,xe2x80x94N(R4)CSN(R4)Het2, aryl or heteroaryl group; Alk3 is a straight or branched C1-6alkylene, C2-6alkenylene or C2-6alkynylene chain, optionally interrupted by one, two or three xe2x80x94Oxe2x80x94 or xe2x80x94Sxe2x80x94 atoms or xe2x80x94S(O)n [where n is an integer 1 or 2] or xe2x80x94N(R8)xe2x80x94groups [where R8 is a hydrogen atom or C1-6alkyl, e.g. methyl or ethyl group]; and m is zero or an integer 1, 2 or 3. It will be appreciated that when two R4 or R7 groups are present in one of the above substituents, the R4 or R7 groups may be the same or different.
When in the group xe2x80x94Alk3(R6a)m m is an integer 1, 2 or 3, it is to be understood that the substituent or substituents R6a may be present on any suitable carbon atom in xe2x80x94Alk3. Where more than one R6a substituent is present these may be the same or different and may be present on the same or different atom in xe2x80x94Alk3. Clearly, when m is zero and no substituent R6a is present the alkylene, alkenylene or alkynylene chain represented by Alk3 becomes an alkyl, alkenyl or alkynyl group.
When R6a is a substituted amino group it may be for example a group xe2x80x94NHR7 [where R7 is as defined above] or a group xe2x80x94N(R7)2 wherein each R7 group is the same or different.
When R6a is a halogen atom it may be for example a fluorine, chlorine, bromine, or iodine atom.
When R6a is a substituted hydroxyl or substituted thiol group it may be for example a group xe2x80x94OR7 or a xe2x80x94SR7 or xe2x80x94SC(xe2x95x90NH)NH2 group respectively.
Esterified carboxyl groups represented by the group R6a include groups of formula xe2x80x94CO2Alk4 wherein Alk4 is a straight or branched, optionally substituted C1-8alkyl group such as a methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl or t-butyl group; a C6-12arylC1-8alkyl group such as an optionally substituted benzyl, phenylethyl, phenylpropyl, 1-naphthylmethyl or 2-naphthylmethyl group; a C6-12aryl group such as an optionally substituted phenyl, 1-naphthyl or 2-naphthyl group; a C6-12aryloxyC1-8 alkyl group such as an optionally substituted phenyloxymethyl, phenyloxyethyl, 1-naphthyl-oxymethyl, or 2-naphthyloxymethyl group; an optionally substituted C1-8alkanoyloxyC1-8alkyl group, such as a pivaloyloxymethyl, propionyloxyethyl or propionyloxypropyl group; or a C6-12aroyloxyC1-8alkyl group such as an optionally substituted benzoyloxyethyl or benzoyloxypropyl group. Optional substituents present on the Alk4 group include R6a substituents described above.
When Alk3 is present in or as a substituent it may be for example a methylene, ethylene, n-propylene, i-propylene, n-butylene, i-butylene, s-butylene, t-butylene, ethenylene, 2-propenylene, 2-butenylene, 3-butenylene, ethynylene, 2-propynylene, 2-butynylene or 3-butynylene chain, optionally interrupted by one, two, or three xe2x80x94Oxe2x80x94 or xe2x80x94Sxe2x80x94, atoms or xe2x80x94S(O)xe2x80x94, xe2x80x94S(O)2xe2x80x94 or xe2x80x94N(R8)xe2x80x94 groups.
Aryl or heteroaryl groups represented by the groups R6a or R7 include mono- or bicyclic optionally substituted C6-12 aromatic or C1-9 heteroaromatic groups as described above for the groups R1 and Het. The aromatic and heteroaromatic groups may be attached to the remainder of the compound of formula (1) by any carbon or hetero e.g. nitrogen atom as appropriate.
When xe2x80x94NHet1 or xe2x80x94Het2 forms part of a substituent R6 each may be for example an optionally substituted pyrrolidinyl, pyrazolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, piperidinyl or thiazolidinyl group. Additionally Het2 may represent for example, an optionally substituted cyclopentyl or cyclohexyl group. Optional substituents which may be present on -NHet1 or xe2x80x94Het2 include those R5 substituents described above.
Particularly useful atoms or groups represented by R6 include fluorine, chlorine, bromine or iodine atoms, or C1-6alkyl, e.g. methyl, ethyl, n-propyl, i-propyl, n-butyl or t-butyl, optionally substituted phenyl, pyridyl, pyrrolyl, furyl, thiazolyl, or thienyl, C1-6alkylamino, e.g. methylamino or ethylamino, C1-6hydroxyalkyl, e.g. hydroxymethyl or hydroxyethyl, carboxyC1-6alkyl, e.g. carboxyethyl, C1-6alkylthio e.g. methylthio or ethylthio, carboxyC1-6alkylthio, e.g. carboxymethylthio, 2-carboxyethylthio or 3-carboxyxe2x80x94propylthio, C1-6alkoxy, e.g. methoxy or ethoxy, hydroxyC1-6alkoxy, e.g. 2-hydroxyethoxy, optionally substituted phenoxy, pyridyloxy, thiazolyoxy, phenylthio or pyridylthio, C5-7cycloalkoxy, e.g. cyclopentyloxy, haloC1-6alkyl, e.g. trifluoromethyl, haloC1-6alkoxy, e.g. trifluoromethoxy, C1-6alkylamino, e.g. methylamino or ethylamino, amino (xe2x80x94NH2), aminoC1-6alkyl, e.g. aminomethyl or aminoethyl, C1-6dialkylamino, e.g. dimethylamino or diethylamino, C1-6alkylaminoC1-6alkyl, e.g. ethylamino ethyl, C1-6dialkylaminoC1-6alkyl, e.g. diethylaminoethyl, aminoC1-6alkoxy, e.g. aminoethoxy, C1-6alkylaminoC1-6alkoxy, e.g. methylaminoethoxy, C1-6dialkylaminoC1-6alkoxy, e.g. dimethylaminoethoxy, diethylaminoethoxy, isopropylaminoethoxy, or dimethylaminopropoxy, imido, such as phthalimido or naphthalimido, e.g. 1,8-naphthalimido, nitro, cyano, amidino, hydroxyl (xe2x80x94OH), formyl [HC(O)xe2x80x94], carboxyl (xe2x80x94CO2H), xe2x80x94CO2Alk4 [where Alk4 is as defined above], C1-6 alkanoyl e.g. acetyl, optionally substituted benzoyl, thiol (xe2x80x94SH), thioC1-6alkyl, e.g. thiomethyl or thioethyl, xe2x80x94SC(xe2x95x90NH)NH2, sulphonyl (xe2x80x94SO3H), C1-6alkylsulphonyl, e.g. methylsulphonyl, aminosulphonyl (xe2x80x94SO2NH2), C1-6alkylaminosulphonyl, e.g. methylaminosulphonyl or ethylaminosulphonyl, C1-6dialkylaminosulphonyl, e.g. dimethylaminosulphonyl or diethylaminosulphonyl, phenylaminosulphonyl, carboxamido (xe2x80x94CONH2), C1-6alkylaminocarbonyl, e.g. methylaminocarbonyl or ethylaminocarbonyl, C1-6dialkylaminocarbonyl, e.g. dimethylaminocarbonyl or diethylaminocarbonyl, aminoC1-6alkylaminocarbonyl, e.g. aminoethylaminocarbonyl, C1-6dialkylaminoC1-6alkylaminoxe2x80x94carbonyl, e.g. diethylaminoethylaminocarbonyl, aminocarbonylamino, C1-6alkylaminocarbonylamino, e.g. methylaminocarbonylamino or ethylaminocarbonylamino, C1-6dialkylaminocarbonylamino, e.g. dimethylaminocarbonylamino or diethylaminocarbonylamino, C1-6alkylaminocabonylC1-6alkylamino, e.g. methylaminocarbonylmethylamino, aminothiocarbonylamino, C1-6alkylaminothiocarbonylamino, e.g. methylaminothiocarbonylamino or ethylaminothiocarbonylamino, C1-6dialkylaminothiocarbonylamino, e.g. dimethylaminothiocarbonylamino or diethylaminothiocarbonylamino, C1-6alkylaminothiocarbonylC1-6alkylamino, e.g. ethylaminothiocarbonylmethylamino, xe2x80x94CONHC(xe2x95x90NH)NH2, C1-6alkylsulphonylamino, e.g. methylsulphonylamino or ethylsulphonylamino, C1-6dialkylsulphonylamino, e.g. dimethylsulphonylamino or diethylsulphonylamino, optionally substituted phenylsulphonylamino, aminosulphonylamino (xe2x80x94NHSQ2NH2), C1-6alkylaminosulphonylamino, e.g. methylaminosulphonyl-amino or ethylaminosulphonylamino, C1-6dialkylaminosulphonylamino, e.g. dimethylaminosulphonylamino or diethylaminosulphonylamino, optionally substituted morpholinesulphonylamino or morpholinesulphonylC1-6alkylamino, optionally substituted phenylaminosulphonylamino, C1-6alkanoylamino, e.g. acetylamino, aminoC1-6alkanoylamino e.g. aminoacetylamino, C1-6dialkylaminoC1-6alkanoyl-amino, e.g. dimethylaminoacetylamino, C1-6alkanoylaminoC1-6alkyl, e.g. acetylaminomethyl, C1-6alkanoylaminoC1-6alkylamino, e.g. acetamidoethylamino, C1-6alkoxycarbonylamino, e.g. methoxycarbonylamino. ethoxycarbonylamino or t-butoxycarbonylamino or optionally substituted benzyloxy, pyridylmethoxy, thiazolylmethoxy, benzyloxycarbonylamino, benzyloxycarbonylaminoC1-6alkyl e.g. benzyloxycarbonylaminoethyl benzothio: pyridylmethylthio or thiazolylmethylthio groups.
Where desired, two R6 substituents may be linked together to form a cyclic group such as a cyclic ether, e.g. a C1-6alkylenedioxy group such as methylenedioxy or ethylenedioxy.
It will be appreciated that where two or more R6 substituents are present, these need not necessarily be the same atoms and/or groups. In general, the substituent(s) may be present at any available ring position in the heteroaromatic group represented by Het.
The presence of certain substituents in the compounds of formula (1) may enable salts of the compounds to be formed. Suitable salts include pharmaceutically acceptable salts, for example acid addition salts derived from inorganic or organic acids, and salts derived from inorganic and organic bases.
Acid addition salts include hydrochlorides, hydrobromides, hydroiodides, alkylsulphonates, e.g. methanesulphonates, ethanesulphonates, or isothionates, arylsulphonates, e.g. p-toluenesulphonates, besylates or napsylates, phosphates, sulphates, hydrogen sulphates, acetates, trifluoroacetates, propionates, citrates, maleates. fumarates, malonates, succinates, lactates, oxalates, tartrates and benzoates.
Salts derived from inorganic or organic bases include alkali metal salts such as sodium or potassium salts, alkaline earth met al salts such as magnesium or calcium salts, and organic amine salts such as morpholine, piperidine, dimethylamine or diethylamine salts.
Particularly useful salts of compounds according to the invention include pharmaceutically acceptable salts, especially acid addition pharmaceutically acceptable salts.
R in compounds of the invention is preferably a xe2x80x94CO2H group.
When present, the aliphatic chain represented by Alk1 in compounds of the invention is preferably a xe2x80x94CH2xe2x80x94 chain.
Alk2 in compounds of formula (1) is preferably a xe2x80x94CH2xe2x80x94 chain and m is preferably an integer 1. In compounds of this type, the carbon atom to which Alk2 and R are attached forms a chiral centre and is preferably in the L configuration.
R2 in compounds of formula (1) is preferably a hydrogen atom.
R3 in compounds of the invention is preferably a hydrogen atom.
In general in compounds of the invention xe2x80x94(Alk1)n(L1)sxe2x80x94 is preferably CH2Oxe2x80x94, xe2x80x94SO2NH, xe2x80x94C(O)Oxe2x80x94 or xe2x80x94CON(R4)xe2x80x94 and is especially xe2x80x94CONHxe2x80x94.
In general in compounds of the invention the group R1 is preferably an optionally substituted aromatic or heteroaromatic group. Particularly useful groups of these types include optionally substituted phenyl, pyridyl or pyrimidinyl groups, particularly those in which the substituent when present is an atom or group xe2x80x94L2(CH2)pL3(Rc)q as described above. Each substituent may be present on any available ring carbon or nitrogen atom.
The aromatic group represented by Ar in compounds of formulae (1) and (1a) is preferably on optionally substituted phenyl group. Each optional substituent when present is preferably an atom or group R6 as defined above.
A particularly useful class of compounds according to the invention has the formula (1b) 
wherein xe2x80x94Wxe2x95x90 is xe2x80x94CHxe2x95x90 or xe2x80x94Nxe2x95x90, R9 and R10, which may be the same or different, is each a xe2x80x94L2(CH2)pL3(Rc)q atom or group as generally and particularly defined above, and Alk1, r, L1, s, Ra, Rb, R and Ar are as generally and particularly defined above, and the salts, solvates, hydrates and N-oxides thereof.
It will be appreciated that the various preferences stated above in relation to groups present in compounds of formulae (1) and (1a) apply equally to the same groups when present in compounds of formula (1b).
Additionally, in compounds of formula (1b) xe2x80x94(Alk1)r(L1)rxe2x80x94 is preferably a xe2x80x94CH2O or xe2x80x94CON(R4)xe2x80x94 group and is especially a xe2x80x94CONHxe2x80x94 group.
Ar is preferably an optionally substituted phenyl group. Particularly useful compounds of formula (1b) are those wherein Ar is a 2- , 3- or 4-monosubstituted or a 2,6-disubstituted phenyl group.
One of R9 or R10 in compounds of formula (1a) may be for example a hydrogen atom and the other a substituent L2(CH2)pL3(Rc)q in which Rc is not a covalent bond and p is zero, but preferably each of R9 and R10 is a substituent xe2x80x94L(2CH2)pL3(Rc)q where Rc is as just defined. Particularly useful R9 or R10 substituents include a hydrogen atom or halogen atom, especially fluorine or chlorine atoms, or a methyl, ethyl, methoxy, ethoxy, xe2x80x94CF3, xe2x80x94OH, xe2x80x94CN, xe2x80x94NO2, xe2x80x94NH2, xe2x80x94NHCH3, xe2x80x94N(CH3)2, xe2x80x94COCH3, xe2x80x94SCH3, xe2x80x94CO2H or xe2x80x94CO2CH3 group.
Particularly useful compounds according to the invention include the following:
(N-2,6-Dimethoxybenzoyl)-[O-(3,5-dichloro-4-pyridinyl)methyl]-L-tyrosine; 2-Carboxybenzoyl-(Nxe2x80x2-3,5-dichloroisonicotinoyl)-L-4-aminophenylalanine;
(N-2,6-Dimethoxybenzoyl)-(Nxe2x80x2-3,5-dichloroisonicotinoyl)-L-4-aminophenylalanine;
(N-3-Carboxybenzoyl)-(Nxe2x80x2-3,5-dichloroisonicotoninoyl)-L-4-aminophenyalanine;
(N-4-Carboxybenzoyl)-(Nxe2x80x2-3,5-dichloroisonicotinoyl)-L-4-aminophenylalanine;
(N-2-t-Butoxycarbonylbenzoyl)-(Nxe2x80x2-3,5-dichloroisonicotinoyl)-L-4-aminophenylalanine;
(N-3-Cyanobenzoyl)-(Nxe2x80x2-3,5-dichloroisonicotinoyl)-L-4-aminophenylalanine;
[N-3-(1-H-Tetrazol-5-yl)benzoyl]-(Nxe2x80x2-3,5-dichloroisonicotinoyl)-L-4-aminophenylalanine;
[N-(3-Methoxycarbonylbenzoyl)]-(Nxe2x80x2-3,5-dichloroisonicotinoyl)-L-4-aminophenylalnine;
and the salts, solvates, hydrates and N-oxides thereof.
The compounds of formulae (1), (1a) and (1b) may be prepared by a number of processes as generally described below and more specifically in the Examples hereinafter. In the following process description, the symbols R1-R3, L1, Alk1, Ra, Rb, Alk2, m, r, s and Ar when used in the formulae depicted are to be understood to represent those groups described above in relation to formula (1) unless otherwise indicated. In the reactions described below, it may be necessary to protect reactive functional groups, for example hydroxy, amino, thio or carboxy groups, where these are desired in the final product, to avoid their unwanted participation in the reactions. Conventional protecting groups may be used in accordance with standard practice [see, for example, Green, T. W. in xe2x80x9cProtective Groups in Organic Synthesisxe2x80x9d, John Wiley and Sons, 1991]. In some instances, deprotection may be the final step in the synthesis of the desired compound and the processes described hereinafter are to be understood to extend to such removal of protecting groups. For convenience, the processes described below all refer to the preparation of a compound of formula (1) but clearly the description applies equally to the preparation of compounds of formulae (1a) and (1b).
Thus a compound of formula (1) may be obtained by hydrolysis of an ester of formula (2): 
where R11 is an alkyl group.
The hydrolysis may be performed using either an acid or a base depending on the nature of R9, for example an organic acid such as trifluoracetic acid or an inorganic base such as lithium hydroxide optionally in an aqueous organic solvent such as an amide, e.g. a substituted amide such as dimethylformamide, an ether, e.g. a cyclic ether such as tetrahydrofuran or dioxane or an alcohol, e.g. methanol at around ambient temperature. Where desired, mixtures of such solvents may be used.
Esters of formula (2) may be prepared by coupling an amine of formula 3): 
(where R11 is as just described) or a salt thereof with an acid of formula (4):
ArCO2Hxe2x80x83xe2x80x83(4)
or an active derivative thereof.
Active derivatives of acids of formula (4) include anhydrides, esters and halides. Particular esters include pentafluorophenyl or succinyl esters.
The coupling reaction may be performed using standard conditions for reactions of this type. Thus for example the reaction may be carried out in a solvent, for example an inert organic solvent such as an amide, e.g. a substituted amide such as dimethylformamide, an ether, e.g. a cyclic ether such as tetrahydrofuran, or a halogenated hydrocarbon, such as dichloromethane, at a low temperature, e.g. around xe2x88x9230xc2x0 C. to around ambient temperature, optionally in the presence of a base, e.g. an organic base such as an amine, e.g. triethylamine, pyridine, or dimethylaminopyridine, or a cyclic amine, such as N-methylmorpholine.
Where an acid of formula (4) is used, the reaction may additionally be performed in the presence of a condensing agent, for example a diimide such as 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide or N,Nxe2x80x2-dicyclohexylcarbodiimide, advantageously in the presence of a catalyst such as a N-hydroxy compound e.g. a N-hydroxytriazole such as 1-hydroxybenzotriazole. Alternatively, the acid may be reacted with a chloroformate, for example ethylchloroformate, prior to reaction with the amine of formula (3).
Intermediates of formulae (2), (3) and (4), or compounds of formula (1), may be manipulated to introduce substituents to aromatic or heteroaromatic groups or modify existing substituents in groups of these types. Typically, such manipulation may involve standard substitution approaches employing for example alkylation, arylation, heteroarylation, acylation, thioacylation, halogenation, sulphonylation, nitration, formylation or coupling reactions. Alternatively, exisitng substituents may be modified for example by oxidation, reduction or cleavage reactions. Particular examples of such reactions are given below. Where these are paticularly described in relation to the generation of the group R1(Alk1)r(L1l)sxe2x80x94, it will be appreciated that each reaction may also be used to introduce or modify R5 and/or R6 substituents in for example Ar groups as appropriate.
Thus in one example, a compound wherein R1(Alk1)r(L1)sxe2x80x94 is a xe2x80x94L1H group may be alkylated, arylated or heteroaryiated using a reagent R1(Alk1)rX in which R1 is other than a hydrogen atom and X is a leaving atom or group such as a halogen atom, e.g. a fluorine, bromine, iodine or chlorine atom or a sulphonyloxy group such as an alkylsulphonyloxy, e.g. trifluoromethylsulphonyloxy or arylsulphonyloxy, e.g. p-toluenesulphonyloxy group,
The reaction may be carried out in the presence of a base such as a carbonate, e.g. caesium or potassium carbonate, an alkoxide, e.g. potassium t-butoxide, or a hydride, e.g. sodium hydride, in a dipolar aprotic solvent such as an amide, e.g. a substituted amide such as dimethylformamide or an ether, e.g. a cyclic ether such as tetrahydrofuran.
In another example, a compound where R1(Alk1)r(L1)s is a xe2x80x94L1H group is a hydrogen atom may be functionalised by acylation or thioacylation, for example by reaction with a reagent R1(Alk1)rL1X [wherein L1 is a xe2x80x94C(O)xe2x80x94, C(S)xe2x80x94, xe2x80x94N(R4)C(O)xe2x80x94 or N(R4)C(S)xe2x80x94 group], in the presence of a base, such as a hydride, e.g. sodium hydride or an amine, e.g. triethylamine or N-methylmorpholine, in a solvent such as a halogenated hydrocarbon, e.g. dichloromethane or carbon tetrachloride or an amide, e.g. dimethylformamide, at for example ambient temperature, or by reaction with R1(Alk1)rCO2H, R1(Alk)4COSH or an activated derivative thereof, for example as described above for the preparation of esters of formula (2).
In a further example a compound may be obtained by sulphonylation of a compound where R1(Alk1)r(L1)s is an xe2x80x94OH group by reaction with a reagent R1(Alk1)rL1Hal [in which L1 is xe2x80x94S(O)xe2x80x94 or xe2x80x94SO2xe2x80x94and Hal is a halogen atom such as chlorine atom] in the presence of a base, for example an inorganic base such as sodium hydride in a solvent such as an amide, e.g. a substituted amide such as dimethylformamide at for example ambient temperature.
In another example, a compound where R1(Alk1)r(L1)s is a xe2x80x94L1H group, may be coupled with a reagent R1 OH (where R1 is other than a hydrogen atom) or R1Alk1 OH in a solvent such as tetrahydrofuran in the presence of a phosphine, e.g. triphenylphosphine and an activator such as diethyl, diisopropyl- or dimethylazodicarboxylate to yield a compound containing a R1(Alk1)rOxe2x80x94 group.
In a further example, ester groups xe2x80x94CO2R4 or xe2x80x94CO2Alk4 in compounds of formula (1) may be converted to the corresponding acid [xe2x80x94CO2H] by acid- or base-catalysed hydrolysis depending on the nature of the grousp R4 or Alk4. Acid- or base-catalysed hydrolysis may be achieved for example by treatment with an organic or inorganic acid, e.g. trifluoroacetic acid in an aqueous solvent or a mineral acid such as hydrochloric acid in a solvent such as dioxane or an alkali metal hydroxide, e.g. lithium hydroxide in an aqueous alcohol, e.g. aqueous methanol.
In a second example, xe2x80x94OR7 [where R7 represents an alkyl group such as methyl group] groups in compounds of formula (1) may be cleaved to the corresponding alcohol xe2x80x94OH by reaction with boron tribromide in a solvent such as a halogenated hydrocarbon, e.g. dichloromethane at a low temperature, e.g. around xe2x88x9278xc2x0 C.
Alcohol [xe2x80x94OH] groups may also be obtained by hydrogenation of a corresponding xe2x80x94OCH2R7 group (where R7 is an aryl group) using a metal catalyst, for example palladium on a support such as carbon in a solvent such as ethanol in the presence of ammonium formate, cyclohexadiene or hydrogen, from around ambient to the reflux temperature. In another example, xe2x80x94OH groups may be generated from the corresponding ester [xe2x80x94CO2Alk4 or CO2R4] or aldehyde [xe2x80x94CHO] by reduction, using for example a complex metal hydride such as lithium aluminium hydride or sodium borohydride in a solvent such as methanol.
In another example, alcohol xe2x80x94OH groups in compounds of formula (1) may be converted to a corresponding xe2x80x94OR3 group by coupling with a reagent R7OH in a solvent such as tetrahydrofuran in the presence of a phosphine, e.g. triphenylphosphine and an activator such as diethyl-, diisopropyl-, or dimethylazodicarboxylate.
Aminosulphonylamino [xe2x80x94NHSO2NH2] groups in compounds of formula (1) may be obtained, in another example, by reaction of a corresponding amine [xe2x80x94NH2] with sulphamide in the presence of an organic base such as pyridine at an elevated temperature, e.g. the reflux temperature.
In a further example amine (xe2x80x94NH2) groups may be alkylated using a reductive alkylation process employing an aldehyde and a borohydride, for example sodium triacetoxyborohyride or sodium cyanoborohydride, in a solvent such as a halogenated hydrocarbon, e.g. dichloromethane, a ketone such as acetone, or an alcohol, e.g. ethanol, where necessary in the presence of an acid such as acetic acid at around ambient temperature.
In a further example, amine [xe2x80x94NH2] groups in compounds of formula (1) may be obtained by hydrolysis from a corresponding imide by reaction with hydrazine in a solvent such as an alcohol, e.g. ethanol at ambient temperature.
In another example, a nitro [xe2x80x94NO2] group may be reduced to an amine [xe2x80x94NH2], for example by catalytic hydrogenation using for example hydrogen in the presence of a metal catalyst, for example palladium on a support such as carbon in a solvent such as an ether, e.g. tetrahydrofuran or an alcohol e.g. methanol, or by chemical reduction using for example a metal, e.g. tin or iron, in the presence of an acid such as hydrochloric acid.
Aromatic halogen substituents in compounds of the invention may be subjected to halogen-metal exchange with a base, for example a lithium base such as n-butyl or t-butyl lithium, optionally at a low temperature, e.g. around xe2x88x9278xc2x0 C., in a solvent such as tetrahydrofuran and then quenched with an electrophile to introduce a desired substituent. Thus, for example, a formyl group may be introduced by using dimethylformamide as the electrophile; a thiomethyl group may be introduced by using dimethyldisulphide as the electrophile.
In another example, sulphur atoms in compounds of the invention, for example when present in the linker group L1 may be oxidised to the corresponding sulphoxide using an oxidising agent such as a peroxy acid, e.g. 3-chloroperoxybenzoic acid, in an inert solvent such as a halogenated hydrocarbon, e.g. dichloromethane, at around ambient temperature. Intermediates of formulae (3) and (4), R1(Alk1)rX, R1(Alk1)rL1X, R1(Alk1)rCO2H, R1OH and R1Alk1OH for use in the above processes are either known compounds or may be prepared from known starting materials by use of analogous processes to those used for the preparation of the known compounds and/or by treating known compounds by one or more of the alkylation, acylation and other manipulations described herein, such as particularly described for the preparation of the Intermediates in the exemplification section hereinafter.
N-oxides of compounds of formula (1) may be prepared for example by oxidation of the corresponding nitrogen base using an oxidising agent such as hydrogen peroxide in the presence of an acid such as acetic acid, at an elevated temperature, for example around 70xc2x0 C. to 80xc2x0 C., or alternatively by reaction with a peracid such as peracetic acid in a solvent, e.g. dichloromethane, at ambient temperature.
Salts of compounds of formula (1) may be prepared by reaction of a compound of formula (1) with an appropriate base in a suit able solvent or mixture of solvents e.g. an organic solvent such as an ether e.g. diethylether, or an alcohol, e.g. ethanol using conventional procedures.
Where it is desired to obtain a particular enantiomer of a compound of formula (1) this may be produced from a corresponding mixture of enantiomers using any suitable conventional procedure for resolving enantiomers.
Thus for example diastereomeric derivatives, e.g. salts, may be produced by reaction of a mixture of enantiomers of formula (1) e.g. a racemate, and an appropriate chiral compound, e.g. a chiral base. The diastereomers may then be separated by any convenient means, for example by crystallisation and the desired enantiomer recovered, e.g. by treatment with an acid in the instance where the diastereomer is a salt.
In another resolution process a racem ate of formula (1) may be separated using chiral High Performance Liquid Chromatography. Alternatively. if desired a particular enantiomer may be obtained by using an appropriate chiral intermediate in one of the processes described above.